The effects of chlorpromazine and secobarbital on matching from sample and discrimination tasks in monkeys

Summary Monkeys were trained in the performance of a matching from sample task and in two simultaneous visual discrimination tasks differing in level of difficulty. In the case of the matching task, four doses each of chlorpromazine and of secobarbital were administered to the animals according to a balanced design. The procedure was then replicated. The results of the matching task indicated that chlorpromazine produced many errors of omission and few errors of commission. The latter kind of error as well as other measures of confused responding were seen primarily with secobarbital. In the case of the visual discriminations, secobarbital produced greater impairment of the more difficult (pattern) task than of the simpler (color) task; chlorpromazine had equivalent effects on the two tasks. The similarity between the secobarbital action and the behavioral consequences of certain cortical lesions in the monkey was discussed.This work was supported by the following grants from the National Institute of Mental Health, Public Health Service: Research Grant MH-12568; Special Fellowship 1-F3-25,128 (Dr. Bakay Pragay); Research Scientist Award 5-KO-5MH-14,915 (Dr. Mirsky); Predoctoral Fellowship 1-F2-NB-32-103 (Dr. Abplanalp).     

The differential effects of chlorpromazine and pentobarbital on two forms of conditioned avoidance behavior in peromyscus maniculatus gracilis

Summary A series of experiments was designed to compare the conditioned behavior of a subspecies of deermouse (Peromyscus maniculatus gracilis) in two response situations: 1. avoidance of shock by climbing a pole, and 2. avoidance of shock by remaining on a non-electrified pan located at grid level. This subspecies is semi-arboreal in its natural habitat. As was expected, an experimentally-induced response analogous to those to which the animal is phenotypically predisposed is rapidly acquired and resistant to spontaneous extinction. Thus, the pole response was acquired more rapidly, was more resistant to extinction, and was less susceptible to suppression by drugs. The stability of such behavior makes mice exhibiting this type of response advantageous for testing the effects of psychotropic drugs. The fact that chlorpromazine may be differentiated from pentobarbital by means of these technics supports this conclusion.Supported by a research grant from the National Institute of Neurological Diseases and Blindness (B-381), National Institutes of Health, U.S. Public Health Service.Portion of a thesis presented by Harold H. Wolf in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of Utah.Predoctoral Fellow 1960–61, National Institute of Mental Health, U.S. Public Health Service.     

Drugs,shock intensity,and the CER

Summary The effects of chronic small doses of reserpine (0.2 mg./kg.) and of chlorpromazine (1.5 mg./kg.) upon the CER were studied using albino rats as subjects. It was found that reserpine reliably reduced the CER at a relatively low shock intensity (0.8 ma.) but, with a more severe shock (1.0 ma.), the results were equivocal. Chlorpromazine inhibited the CER at 1.0 ma. At the dosage and time parameters studied, chlorpromazine induced less depression of VI rate than did reserpine; recovery from reserpine effects was generally more gradual than was recovery from chronic chlorpromazine treatment.This research was supported by Research Grant MY 3363 from the National Institute of Mental Health. The author would like to thank D. X. Freedman, M.D., for providing laboratory facilities and to acknowledge the technical assistance of Miss C. V. Perotti.     

Some observations on the interaction of chlorpromazine and free operant avoidance bursts

Summary Rate of avoidance responding underSidman schedules is normally decreased as a function of increasing doses of chlorpromazine. This change is accompanied by a correlated increase in the shock rate as a function of dose. In a subject displaying a strong pattern of post-shock bursts, the usual effect of chlorpromazine dosage on the shock rate was obtained, but the response rate wasincreased correlatively by doses of less than 1.0 mg./kg., i.m. This resulted from the differential effects of the drug upon avoidance responses and post-shock bursts. Experimental manipulation of the baseline avoidance behavior in this subject through the addition of a schedule providing for punishment of responses occurring in bursts immediately following shocks was successful in eliminating bursts of more than one or two responses. A second chlorpromazine series obtained under this added punishment contingency then yielded a typical dose-effect relation for both response and shock rates under chlorpromazine. The possibility that other apparently “idiosyncratic” dose-response functions in behavioral pharmacology may be due to similar special cases of drug-behavior interaction is discussed. This investigation was supported by Grants MY-2244 and MY-5863 from the National Institutes of Mental Health, U.S. Public Health Service. The writers gratefully acknowledge the continued encouragement and support ofMilton H.Anderson, M. D., Medical Superintendent, Evansville State Hospital and principal investigator, Grant MY-2244. Chlorpromazine was kindly supplied by Smith, Kline and French Laboratories, Inc., Philadelphia, Pa.     

The nature of performance deficit under secobarbital and chlorpromazine in the monkey

The effects of secobarbital and chlorpromazine were studied in monkeys trained on a continuous, rapidly presented successive discrimination task. The subjects were implanted with epidural electrodes to monitor EEG during drug-induced impairment of performance. The analysis was focussed on the phase of drug effect during which both drugs induced intermittent lapses of responding.EEG and behavioral analysis of events following stimulus onset lead to the conclusion that the mechanism of error occurrence is different under the two drugs. The effect of secobarbital was prominent both in correct and incorrect trials; input, integration and output processes seemed to be functional but slowed down. This was inferred from the presence of EEG arousal, late or abortive motor responses (in the case of errors) and prolonged reaction time of correct responses. In contrast to this general, even effect, CPZ affected the performance in an all-or-none fashion. Periods of normal functioning (i.e., correct responses with moderately increased average reaction time) alternated with complete absence of responsiveness including the EEG arousal reaction. These findings support the view that secobarbital suppresses the behavior by affecting the level of wakefulness and thus impairing the functional condition of the whole central nervous system; chlorpromazine on the other hand exerts its effect by selectively blocking input processes subserving the EEG and behavioral arousal.Supported by Grant MH-12568 from the National Institute of Mental Health, Public Health Service.Research Scientist Awardee (5-K-5-MH-14, 915) of the National Institute of Mental Health.     

Chlorpromazine and avoidance: A genetic analysis

Chlorpromazine exerts a significantly higher impairment on the performance of C57BL/6By than on BALB/cBy inbred mice pretrained in an active avoidance task. The effects of the drug on this measure assessed in these two strains, their reciprocal F₁ hybrids, their recombinant inbred strains, and two C57BL/6By congenic lines indicate that at least two genes modulate the action of chlorpromazine on avoidance behavior. It was possible to characterize one of the loci modulating the effect of chlorpromazine on avoidance performance. We assign the symbol Cpz. The locus is in chromosome 9, Linkage Group II.The Jackson Laboratory is fully accredited by the American Association for Accreditation of Laboratory Animal Care.This study was supported by a grant from the Italian and French National Research Councils, in part by NIH Research Grant HD 05860 from the National Institute of Child Health and Human Development, and in part by NIH Research Grant GM 15574 from the National Institute of General Medical Sciences.     

Effects of drugs on avoidance behavior

Summary Thirty-five rats were observed on two occasions in a novel environment, and then trained in a Sidman avoidance response. Each was tested in the avoidance situation following injection of a single dose of chlorpromazine, d-amphetamine, atropine, and scopolamine.Effects of the drugs on avoidance behavior were similar to those reported in earlier studies. Changes from baseline values in response rate and shock rate under drug were found to be the best measures of individual rats' susceptibilities to the drugs.Susceptibilities to the response-stimulating effects of amphetamine, atropine and scopolamine were highly interrelated, but susceptibility to chlorpromazine was distinct. Susceptibility to chlorpromazine was greatest in rats with high baseline rates of responding and shock avoidance. Change in shock rates after administration of stimulant drugs was greatest in rats with high baseline rates of shocks (poor avoiders). Increase in response rate under the stimulants was greatest in animals that tended to groom and freeze in the novel environment, rather than boldly exploring.The effects of the stimulants are discussed in terms of a model relating to the balance of excitation versus inhibition in response to aversive stimulation. Differences in baseline avoidance rates and in susceptibilityThis experiment was supported by grant MH-04139 from The National Institute of Mental Health and by The California Department of Mental Hygiene.     

EEG correlates of impaired attention performance under secobarbital and chlorpromazine in the monkey

The effects of secobarbital and chlorpromazineupon behavior in a continuous, rapidly presented successive (go-no go) discrimination (attention) task were evaluated in six Macaca mulatta monkeys. Simultaneous monitoring of EEG activity from epidural and subcortical electrodes permitted an evaluation of the nature of altered central nervous system events during erroneous performance (errors of omission) on this task. The computer-assisted analysis of pre-stimulus and post-stimulus EEG frequency activity (baseline crossings) suggests that the best measure of attentive behavior from the pre-stimulus EEG is percentage of beta 2 (25–40 cps) activity. No difference could be observed between drugs or among cerebral placements in this regard. This was determined by comparing measures of EEG frequency, pooled for a given test period, with performance from the same test period. On a trial-by-trial basis, however, the beta 2 measure in the pre-stimulus epoch failed to distinguish correct responses from errors of omission.Separation between correct responses and errors of omission is possible if comparisons are made between the changes in percentage of beta 2 activity in the pre-stimulus vs. post-stimulus epochs. For both drugs, the largest absolute change in beta 2 pre- vs. post-stimulus occurs with correct positive trials and the smallest change with correct negative trials. For secobarbital, no difference could be detected between correct and incorrect positive trials. For chlorpromazine, however, there was significantly less change in beta 2 for incorrect positive than for correct positive trials. The results were interpreted in terms of the hypothesis that secobarbital produces errors by depression of the general level of activation whereas chlorpromazine acts by reducing the sensory input which is necessary for correct discrimination performance.Some of these results were presented to the IXth Meeting of the Collegium Internationale Neuropsychopharmacologicum, Paris, France, July, 1974. Supported by USPHS grant No. MH 12568 from the National Institute of Mental Health. The authors are grateful to Dr. Eva Bakay Pragay for her wise counsel.Research Scientist Awardee K05 14915 of the National Institute of Mental Health.     

The effects of some psychotropic drugs on conditioned avoidance and aggressive behaviors

Summary Chlorpromazine, chlordiazepoxide, meprobamate, and pentobarbital were evaluated for their ability to alter 3 behaviors: 1. unconditioned escape, 2. conditioned avoidance, and 3. isolation-induced aggression, in the same species of mouse. A comparison of the dose of each drug necessary to alter these behaviors revealed quantitative differences between the drugs by which chlorpromazine and chlordiazepoxide may be differentiated from each other as well as from pentobarbital and meprobamate.Supported by a research grant from the National Institute of Mental Health (MH-07397-02), U.S. Public Health Service.Portion of a thesis presented by Henry F. Cole in partial fulfillment of the requirements for the Master of Science Degree at The Ohio State University.Predoctoral Fellow 1964–65, National Institutes of Health, U.S. Public Health Service.     

On the dissimilar effects of drugs on the digit symbol substitution and continuous performance tests

Summary A tentative hypothesis is presented to account for the dissociation of the effects of various centrally-acting drugs and other agents on performance of the Continuous Performance Test (C.P.T.) and the Digit Symbol Substitution Test (D.S.S.T.): L.S.D., secobarbital, pentobarbital meprobamate and phenobarbital produced significantly greater impairment of the D.S.S.T. than of the C.P.T., while chlorpromazine, sleep deprivation and centrencephalic epilepsy had the reverse effect. Psychological, neurophysiological, electroencephalographic and neuropharmacological data were cited which suggested that the tests were affected differently because they are dependent upon the functioning of somewhat different neural organizations which are, in turn, differentially sensitive to the action of various centrally-active agents.The studies referred to in this paper involving the Digit Symbol Substitution and Continuous Performance Tests were conducted in the Laboratory of Clinical Science, and in the Section on Neuropsychology, Laboratory of Psychology, National Institute of Mental Health, and in the Surgical Neurology Branch of the National Institute of Neurological Diseases and Blindness. The authors wish to express their appreciation to the numerous members of the staff of these laboratories who provided advice, assistance and facilities for these studies. Part of the costs of preparing this work for publication were borne by grant M-6015 from the National Science Foundation, grants GMK3-1759 and K3-14 915 from the National Institute of Mental Health and grant 61-241 from the Foundations Fund for Research in Psychiatry.     

Temporary and partial antagonism by l-DOPA of reserpine-induced suppression of a conditioned avoidance response

Summary Mice and rats were trained to avoid shock in a modified shuttle box. Following training the animals were treated with reserpine. The suppression of the conditioned avoidance response induced by reserpine was partially and temporarily reversed by an injection of l-3,4-dihydroxyphenylalanine, and the suppression of locomotor activity was completely antagonized for approximately the same duration.This investigation supported in part by Postdoctoral Fellowship (MPD-10, 562-C3) from the United States Public Health Service, National Institute of Mental Health.The authors wish to thank Miss Anne-Charlotte Lilljeqvist for her expert technical assistance.     

Strain differences in the effects of chlorpromazine and chlordiazepoxide upon active and passive avoidance in mice

Summary Four inbred strains of mice were compared on an active and a passive avoidance task in a two-compartment cage. Active mice were trained to cross frequently between compartments to avoid shock; passive mice were shocked for crossing. Yoked controls in both procedures received shocks at the same time as experimentals. Strains learning the active task well did poorly in the passive task; strains poor in active learning were superior on the passive task. The results support the view that strain differences in avoidance learning are more related to variations in strength of a kinetic drive than to strength of fear. Chlordiazepoxide affected crossings similarly in actively and passively trained Ss; chlorpromazine reduced crossings in actively trained and increased crossings in passively trained Ss. This result is consistent with dual motivational systems differentially susceptible to alteration by administration of drugs. Chlordiazepoxide acts primarily upon kinetic drive; chlorpromazine upon fear.This investigation was supported in part by United States Public Health Service Research Grants MH-01775 and MH-11327 from the National Institute of Mental Health.The author acknowledges the technical assistance of Frank Clark and Jane Harris.The principles of laboratory animal care as promulgated by the American Psychological Association were observed in this study.     

A research note on some of the critical factors on the dissimilar effects of chlorpromazine and secobarbital on the digit symbol substitution and continuous performance tests

Summary The effects of single doses of chlorpromazine and secobarbital on performance of normal subjects on four behavioral tests were compared. The tests were the Continuous Performance Test (CPT), an experimenter-paced test requiring continued vigilence on the part of the subject; the Digit Symbol Substitution Test (DSST), a self-paced, cognitive test; the Subject-Paced Test (SPT), a test designed to include the same visual stimuli as those used in the CPT with the subject having control over the speed of presentation of the visual stimuli: and the Symbol Copying Test (SCT), a test designed to have all the motor, visual, and self-pacing components of the DSST with the cognitive aspect removed.The results support the hypothesis that chlorpromazine causes more decrement in performance than does secobarbital on experimenter-paced tests where sustained attention is necessary. However, on self-paced tests where sustained attention is not necessary, secobarbital causes more decrement in performance than does chlorpromazine. A self-paced test that is sensitive to barbiturates ceases to be a sensitive indicator of barbiturate effects when the cognitive aspect of the test is removed.This research is supported by USPHS Grant MH-03312-04 and GM-K3-1759-C3-A.The authors wish to thankHarold Lee, M. D., Assistant Superintendent at Medfield State Hospital, for his co-operation in both obtaining the subjects and for assuming medical responsibility for the subjects.     

Pharmacological modification of the effects of spaced occipital ablations

Summary Retention of an avoidance response made to the onset of a change in illumination was measured following temporally spaced bilateral ablation of the occipital cortex of the rat. Twelve days were allowed to pass between the ablation of cortex of the two hemispheres. Post-operative retention was superior when the inter-operative interval was spent in the light and noise, except when paired with chronic administration of phenobarbital (30 mg/kg/day). Post-operative retention was minimized when the interoperative interval was spent in dark and quiet, except when paired with chronic administration of d-amphetamine (2 mg/kg/ day).This work was supported by a grant (MH-04539) from the National Institute of Mental Health to W. Isaac.This work was done while on a Post Doctoral Fellowship, National Institute of Mental Health     

Social influences on the response to drugs

Summary Ninety male albino rats were assigned to three groups of 30 animals each. Ss in each group were housed individually but were paired for testing. One S in each pair received either saline, amphetamine, or chlorpromazine depending upon the group. Pairs of animals, consisting of one treated and one non-treated rat, were placed in an observation box and a number of categories of behavior observed and recorded. It was found that the behavior of the non-treated rats, in the case of the amphetamine and chlorpromazine groups, was modified. In the amphetamine group the behavior of the non-treated rats essentially mirrored the behavior of the treated animals. In the chlorpromazine group the primary change in the non-treated animals was in the category of active social behavior where they demonstrated significantly more of this type behavior than did the treated rats. There were no significant differences in behavior shown between the treated and non-treated animals in the saline group.This research was supported by research grant MH-08407-01 from the National Institute of Mental Health. The authors wish to express their gratitude to Lesley Diehl and Linda Dekker for their aid in collecting data in this investigation.     

Brain and heart catecholamine levels after l-Dopa administration in reserpine treated mice: Correlations with a conditioned avoidance response

Summary Mice were tested with reserpine before receiving an injection of l-DOPA. At various times after the l-DOPA injection they were sacrificed and the brains and hearts were analyzed for their catecholamine content. Effects on the conditioned avoidance response were further analyzed using reserpine and l-DOPA, and the correlations between the two were discussed.United States Public Health Service Postdoctoral Fellow (MPD-10, 562-C 3), National Institute of Mental Health.This research was supported by the United States Air Force under Grant No. AF-EOAR 63-14 and monitored by the European Office, Office of Aerospace Research (to A. Carlsson).     

Facilitating effects of some chlorpromazine-d-amphetamine mixtures on avoidance learning

The effects of several chlorpromazine-d-amphetamine mixtures on discriminated avoidance learning in rats have been studied and compared with the effects of d-amphetamine alone, and it has been found that some of these mixtures increase shock avoidance very significantly. The different mixtures cannot be compared on the basis of the same dose ratio, but some of the observed effects can probably be explained in terms of more or less sustained brain levels of d-amphetamineThe combined treatment of 1 mg/kg chlorpromazine and 1 mg/kg d-amphetamine is one of the most effective and an increase of conditioned responses and a decrease of interresponses is observed in this group as compared with the corresponding d-amphetamine 1 mg/kg group. The significance of these findings and the possible sources of this especial behavioural interaction of the two drugs are discussed.A preliminary report of this study was presented at the 7th International C.I.N.P. Congress, Praha, August 1970.With the technical assistance of Miss M^a Luz de Toro.     

Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition

Rationale The nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signal transduction pathway has been implicated in some forms of learning and memory. Recent findings suggest that inhibition of phosphodiesterase (PDE) enzymes that degrade cGMP may have memory-enhancing effects. Objectives We examined whether treatment with sildenafil citrate, a PDE type 5 inhibitor, would attenuate a learning impairment induced by inhibition of NO synthase [60 mg/kg N ^ω-nitro-l-arginine methyl ester (l-NAME), i.p.]. Methods Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and, on the next day, received 15 training trials in a 14-unit T-maze, a task that has been shown to be sensitive to aging and impairment of central NO signaling systems. Combined treatments of l-NAME or saline and sildenafil (1.0, 1.5, 3.0, or 4.5 mg/kg, i.p.) or vehicle were given 30 and 15 min before training, respectively. Behavioral measures of performance included entries into incorrect maze sections (errors), run time from start to goal (latency), shock frequency, and shock duration. Results Statistical analysis revealed that l-NAME impaired maze performance and that sildenafil (1.5 mg/kg) significantly attenuated this impairment. Control experiments revealed that administration of l-NAME alone did not significantly increase latencies in a one-way active avoidance test and that different doses of sildenafil alone did not significantly alter complex maze performance. Conclusions The results indicate that sildenafil may improve learning by modulating NO–cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease. M. Jimenez and D. Sierra-Mercado, Jr., were supported by Minority Access to Research Careers grants NIGMS 08253 and NIGMS 07717.     

The effects of chlorpromazine and secobarbital on the reaction times of chronic schizophrenics

Summary Twelve male schizophrenics were given a simple visual reaction time test (RT) after single doses and chronic (11 days) administration of chlorpromazine and secobarbital. RT was tested under two conditions: irregular, in which preparatory intervals were presented randomly, and regular, in which the same preparatory intervals were given in consecutive order. Results under single doses indicated that secobarbital reduced intra-individual variability, while chlorpromazine did not significantly affect performance. Results under chronic administration indicated that neither drug had a significant effect on RT performance. These findings are different from those obtained by other investigators who have observed facilitation in schizophrenic psychomotor performance after chlorpromazine, and deficit in performance after barbiturates.This study is a revision of part of a dissertation submitted in partial fulfillment of the requirements for the degree Master of Arts, from the Catholic University of America, August 1957, by the senior author. Thanks are due Dr. John W, Stafford, who served as thesis advisor.This study was part of an N.I.M.H. research project run at St. Elizabeths Hospital, Washington, D.C., under the direction of the junior author, and reported elsewhere (Kornetsky, Pettit, Wynne, and Evarts 1959).This paper was presented in part at the 1958 meetings of the American Psychological Association.     

Evaluation of trifluperidol in chronic schizophrenia

Summary Trifluperidol, a new butyrophenone compound, was evaluated in chronic schizophrenic women under conditions of a controlled clinical trial. Within this framework significant drug effects associated with the standard drug, chlorpromazine, attested to the sensitivity of the experiment, while trifluperidol, the experimental drug, was shown to be an antipsychotic agent at least equally as effective as the standard.The placebo group tended to deteriorate on all measures. This trend did not differ significantly from a similar trend in a group of subjects receiving neither placebo nor active treatment. The most likely explanation for this deterioration is thought to be an inadequate preliminary dry-out period, although other influences affecting all subjects adversely can not be ruled out.The demonstration of significant drug:placebo differences was dependent in part upon the presence of the negative change in the placebo group. Failure to include a control group in the present study would have precluded the demonstration of statistically significant drug effects.Triperidol^®, McNeil Laboratories, Inc., Fort Washington, Pennsylvania.From the Department of Medicine, and the Experimental Therapeutics Unit. University of Oklahoma Medical Center and Central State Griffin Memorial Hospital, Norman, Oklahoma.Presented in part to the American College of Clinical Pharmacology and Chemotherapy, Chicago, Illinois, November 4, 1965, an abstract of which appeared in Journal of New Drugs, July–August, 1965.This study was supported in part by grants MH-04260 and MH-11666 from the National Institute of Mental Health, United States Public Health Service, Bethesda, Maryland, and a grant in aid from the McNeil Laboratories, Inc., Fort Washington, Pennsylvania. Statistical analyses were carried out in collaboration with the Biostatistical Unit and Computer Facility, Department of Preventive Medicine and Public Health, University of Oklahoma Medical Center, Oklahoma City, Oklahoma.The authors are indebted to Kit C. Farwell, Ph. D., and Lee Little, Ph. D., for a part of the psychological testing; to William H. Dickinson, B. A., for a part of the psychological testing and help with the statistical analysis; to Mrs. Agnes Barkett, R. N., and the Ward Staff for behavior ratings and patient care.